This invention relates to implantable graft constructs suitable for various medical applications and the process for producing such graft constructs. More specifically, purified submucosa is used to form tubular multi-laminate constructs of varying diameter. The graft constructs have applications as arterial and venous grafts, ureter and urethra replacements, and as various ducts and shunts.
Researchers in the surgical arts have been working for many years to develop new techniques and materials for use as grafts to replace or repair damaged or diseased tissue structures, particularly bones and connective tissues, such as ligaments and tendons, and to hasten fracture healing. It is very common today, for instance, for an orthopedic surgeon to harvest a patellar tendon of autogenous or allogenous origin for use as a replacement for a torn cruciate ligament. The surgical methods for such techniques are well known. Further, it has become common for surgeons to use implantable prostheses formed from plastic, metal and/or ceramic materials for reconstruction or replacement of physiological structures. Yet, despite their wide use, presently available surgically implanted prostheses present many attendant risks to the patient. Therefore, surgeons are in need of a non-immunogenic, high tensile strength graft material which can be used for the surgical repair of bone, tendons, ligaments and other functional tissue structures.
More recently researchers have been working to develop biological tissues for use as implants and for use in the repair of damaged or diseased tissues, since plastic and polymer materials have drawbacks in these medical applications. While plastics and polymers may have some desirable mechanical properties (e.g., tensile strength), plastics have been found to become infected and in vascular applications plastics have been reported as inducing thrombogenesis.
Tubular prostheses made from natural tissues have been widely used in recent years in the surgical repair and replacement of diseased or damaged blood vessels in human patients. Natural tissue prostheses fall into three general classes: Autogenous, homologous, and heterologous prostheses. Autogenous material tissue prostheses are prepared from tissues taken from the patient""s own body (e.g., saphenous vein grafts). Use of such prostheses eliminates the possibility of rejection of the implanted prosthesis, but requires a more extensive and time-consuming surgical intervention with attendant risks to the patient. Homologous natural tissue prostheses are prepared from tissue taken from another human, while heterologous natural tissue prosthesis are prepared from tissue taken from a different species. The use of homologous and heterologous umbilical cord vessels as, e.g., vascular and ureteral prostheses are disclosed in U.S. Pat. Nos. 3,894,530; 3,974,526; and 3,988,782.
In addition, autogenous vascular prostheses prepared from sheets of pericardial tissue have been disclosed by Yoshio Sako, xe2x80x9cPrevention of Dilation in Autogenous Venous and Pericardial Grafts in the Thoracic Aorta,xe2x80x9d Surgery, 30, pp. 148-160 (1951) and by Robert G. Allen and Francis H. Cole, Jr., xe2x80x9cModified Blalock Shunts Utilizing Pericardial Tube Grafts,xe2x80x9d Jour. Pediatr. Surg., 12(3), pp. 287-294 (1977). Heterologous vascular prostheses prepared from sheets of porcine pericardial tissue have been disclosed by Ornvold K. et al., xe2x80x9cStructural Changes of Stabilized Porcine Pericardium after Experimental and Clinical Implantation,xe2x80x9d in Proc. Eur. Soc. for Artif. Organs, Vol. VI, Geneva, Switzerland (1979).
The necessary characteristics of a tubular vascular prosthesis are biological compatibility, adequate strength, resistance to infection, resistance to biological degradation, non-thrombogenicity and lack of aneurysm formation. As used in this application, the term biological compatibility means that the prosthesis is non-toxic in the in vivo environment of its intended use, and is not rejected by the patient""s physiological system (i.e., is non-antigenic). Furthermore, it is desirable that the prosthesis be capable of production at an economical cost in a wide variety of lengths, diameters and shapes (e.g., straight, curved, bifurcated), be readily anastomosed to the patient""s body and to other tubular prostheses of the same or different type, and exhibit dimensional stability in use.
As disclosed in U.S. Pat. No. 4,902,508, vascular grafts constructs comprising intestinal submucosa have been previously described and utilized to replace damaged or diseased vascular tissues. More specifically, as disclosed in U.S. patent application Ser. No. 08/916,490, vascular grafts constructs comprising purified tela submucosa have been previously described and utilized to replace damaged or diseased vascular tissues. The vascular graft constructs were prepared by inserting a glass rod of the appropriate diameter into the lumen of the purified submucosa and hand-suturing along the seam of the purified submucosa. The purified submucosa vascular grafts are aseptically fabricated during surgery and typically take a surgeon about one half hour to prepare. Therefore to avoid spending time preparing the graft constructs during surgery, premade, presterilized grafts of different diameters are desirable.
Preparation of a tubular prosthesis of the correct length and shape increases the ease of implantation and enhances the functionality of the implant. For example, a tubular prosthesis that is too long for the intended application may kink after implantation, whereas implantation of a prosthesis that is too short places excessive tension on the anastomoses at its ends, thereby resulting in trauma to said anastomoses. Thus, it would be highly desirable to provide an array of tubular prostheses that vary in diameter and that can be cut transversely to a desired length at any point between its ends without otherwise substantially damaging the prosthesis.
The present invention is directed to a tubular prosthesis comprising purified submucosa and methods for preparing such a prosthesis. Purified submucosa, prepared in accordance with the present invention, has been previously described as a biocompatible, non-thrombogenic graft material that enhances the repair of damaged or diseased host tissues. Numerous studies have shown that warm-blooded vertebrate submucosa is capable of inducing host tissue proliferation, remodeling and regeneration of tissue structures following implantation in a number of in vivo microenvironments including lower urinary tract, body wall, tendon, ligament, bone, cardiovascular tissues and the central nervous system. Upon implantation, cellular infiltration and a rapid neovascularization are observed and the submucosa material is remodeled into host replacement tissue with site-specific structural and functional properties.
Purified submucosa can be obtained from various tissue sources, harvested from animals raised for meat production, including, for example, pigs, cattle and sheep or other warm-blooded vertebrates. More particularly, the purified submucosa is isolated from warm-blooded tissues including the alimentary, respiratory, urinary or genital tracts of warm-blooded vertebrates. In general purified submucosa is prepared from these tissue sources by delaminating the purified submucosa from both the smooth muscle layers and the mucosal layers. The preparation of intestinal submucosa is described and claimed in U.S. Pat. No. 4,902,508, and the preparation of tela submucosa is described and claimed in U.S. patent application Ser. No. 08/916,490, the disclosure of which is expressly incorporated herein by reference.
In accordance with the present invention, an implantable tubular prosthesis comprising purified submucosa is prepared in the shape of a tube. The tubular construct comprises a first sheet of purified submucosa and, optionally, rolled into the shape of a multi-layered tube of purified submucosa and a second sheet of purified submucosa that is wrapped around the tube of purified submucosa. The second sheet of purified submucosa is overlaid onto the tube of purified submucosa so that a first edge is in contact with the purified submucosa and the second opposite edge is either sutured to the first edge or extends over the first edge and is sutured to the second sheet of purified submucosa. The multi-layered tubular graft constructs of the present invention are formed to have fluid-tight seams and can be shaped to match the endogenous tissue to be replaced by the graft construct.
Further in accordance with the present invention, a process is provided for producing an implantable graft construct formed in the shape of a tube having a seam extending longitudinally along the length of the graft wherein the seam has been sealed to resist movement of fluids from the lumen through the seam to the exterior of the tube. The method of forming the purified submucosal tubular constructs of the present invention comprises the steps of:
A. overlaying a sheet of purified submucosa around the circumference of a mandrel to form a tube of purified submucosa having a multi-layered overlapped region;
B. fixing the purified submucosa layers in the overlapped region to one another;
C. (optionally) overlaying a second sheet of purified submucosa onto the tube of purified submucosa to form a second tube of purified submucosa wherein the seam of the second tube of purified submucosa is sealed by sutures; and
D. compressing the layers of purified submucosa under dehydrating conditions.
The present invention allows for the construction of multi-layered tubular graft constructs from sheets of purified submucosa wherein the walls of the formed tubular prosthesis do not contain any perforations that provide a direct passageway from the lumen of the tube to the exterior surface. The multi-layered tubular prostheses of the present invention have sufficient strength and durability to be used in vascular applications without leakage or failure of the tubular prosthesis.